Claims for Patent: 10,428,382

Summary for Patent: 10,428,382

Title:	MiRNA based treatment monitoring in multiple sclerosis
Abstract:	The present invention relates to methods of determining whether a patient responds to a therapeutic treatment of multiple sclerosis (MS), of monitoring the course of multiple sclerosis (MS) in a patient, of determining the risk for a relapse of multiple sclerosis (MS) in a patient, and of adjusting the dose of a therapeutic drug applied for therapeutic treatment of multiple sclerosis in a patient. Said methods are based on the determination of the level of at least one miRNA in a test sample isolated from the patient. The present invention also relates to a method of identifying a compound suitable for the treatment of multiple sclerosis in a patient. Further, the present invention relates to the use of a polynucleotide or a polynucleotide set for detecting a miRNA to determine whether a patient responds to a therapeutic treatment of multiple sclerosis, to monitor the course of multiple sclerosis in a patient, to determine the risk of a relapse of multiple sclerosis in a patient, to adjust the dose of a therapeutic drug applied for therapeutic treatment of multiple sclerosis in a patient, and to identify a compound suitable for the treatment of multiple sclerosis in a patient. Furthermore, the present invention relates to a kit for determining whether a patient responds to a therapeutic treatment of multiple sclerosis, for monitoring the course of multiple sclerosis in a patient, for determining the risk of a relapse of multiple sclerosis in a patient, for adjusting the dose of a therapeutic drug applied for therapeutic treatment of multiple sclerosis in a patient, or for identifying a compound suitable for the treatment of multiple sclerosis in a patient comprising means for determining the level of at least one miRNA in a test sample isolated from a patient.
Inventor(s):	Keller; Andreas (Puttlingen, DE), Beier; Markus (Weinheim, DE), Scheffler; Matthias (Hirschberg, DE), Wendschlag; Anke (Mannheim, DE), Aktas; Orhan (Hilden, DE), Ingwersen; Jens (Dusseldorf, DE), Hartung; Hans-Peter (Dusseldorf, DE), Kury; Patrick (Dusseldorf, DE), Prozorovski; Timour (Dusseldorf, DE)
Assignee:	Hummingbird Diagnostics GmbH (Heidelberg, DE)
Application Number:	14/383,518
Patent Claims:	1. A method of adjusting a therapeutic treatment of Relapsing-Remitting Multiple Sclerosis (RRMS) comprising the step of: (i) determining the level of at least one miRNA in erythrocytes, leukocytes, and thrombocytes isolated from a whole blood sample taken from a patient to whom at least once a drug to be used in said therapeutic treatment is administered or has been administered, wherein the nucleotide sequence of the at least one miRNA is selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 4; and (ii) detecting an increase when the level of the at least one miRNA determined in step (i) is compared to a reference level of the at least one miRNA, which is determined in erythrocytes, leukocytes, and thrombocytes isolated from a whole blood sample taken from the patient prior to the administration of the drug, and subsequently administering to the patient at least once a renewed dose of the drug; or detecting no increase when the level of the at least one miRNA determined in step (i) is compared to the reference level of the at least one miRNA, and subsequently administering to the patient at least once an increased dose of the drug or a different drug. 2. The method of claim 1, wherein the drug is selected from the group consisting of natalizumab, interferon beta 1a, interferon beta 1b, glatiramer acetate, alemtuzumab, fingolimod, dimethylfumarate, and mitoxantrone. 3. The method of claim 2, wherein the whole blood sample is taken from the patient after the first administration of said drug. 4. A method of adjusting treatment of RRMS in a patient comprising the steps of: (i) treating the patient with a drug suitable for RRMS, (ii) determining the level of at least one miRNA in erythrocytes, leukocytes, and thrombocytes isolated from a whole blood sample taken from the patient, wherein the nucleotide sequence of the at least one miRNA is selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 4, and (iii) detecting an increase when the level of the at least one miRNA determined in step (ii) is compared to a reference level of the at least one miRNA, which is determined in erythrocytes, leukocytes, and thrombocytes isolated from a whole blood sample taken from the patient prior to the administration of the drug, and subsequently administering to the patient at least once a renewed dose of the drug; or detecting no increase when the level of the at least one miRNA determined in step (ii) is compared to the reference level of the at least one miRNA, and subsequently administering to the patient at least once an increased dose of the drug or a different drug. 5. The method of claim 4, wherein the level of the miRNA is the expression level of the miRNA that is determined by nucleic acid hybridization or nucleic acid amplification and wherein (a) the nucleic acid hybridization is performed using a microarray/biochip or beads, or using in situ hybridization, and/or (b) the nucleic acid amplification is performed using real-time PCR. 6. A method of treating a patient suffering from RRMS with natalizumab comprising the steps of: (i) determining the level of at least one miRNA in erythrocytes, leukocytes, and thrombocytes isolated from a whole blood sample taken from a patient suffering from RRMS, wherein the nucleotide sequence of the at least one miRNA is selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 4, and (ii) detecting a decrease when the level of the at least one miRNA determined in step (i) is compared to a reference level of the at least one miRNA in healthy controls, and (iv) treating said patient with natalizumab. 7. A method of treating RRMS in a patient comprising the steps of: (i) isolating a whole blood sample from a patient who has been administered a drug for treating RRMS, (ii) determining the level of at least one miRNA from erythrocytes, leukocytes and thrombocytes isolated from the whole blood sample, wherein the at least one miRNA is selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 4, and (iii) detecting an increase when the level of the at least one miRNA determined in step (ii) is compared to a reference level of the at least one miRNA, which has been determined prior to the administration of the drug to the patient, and subsequently continuing said treatment of the patient; or detecting no increase when the level of the at least one miRNA determined in step (ii) is compared to the reference level of the at least one miRNA, and subsequently discontinuing said treatment of the patient. 8. The method of claim 7, wherein the drug is selected from the group consisting of natalizumab, interferon beta 1a, interferon beta 1b, glatiramer acetate, alemtuzumab, fingolimod, dimethylfumarate, and mitoxantrone. 9. The method of claim 7, wherein the determination of the level of the at least one miRNA from the extracted total RNA comprises: (a) transcribing the extracted total RNA into cDNA, and (b) amplifying and determining the cDNA by qRT-PCR. 10. The method of claim 7, where an at least 1.2 fold increase of the level of the at least one miRNA indicates that the patient responds to said treatment. 11. The method of claim 6, wherein the level of the at least one miRNA is determined in the total RNA isolated from the erythrocytes, leukocytes, and thrombocytes. 12. The method of claim 7, wherein the level of the at least one miRNA is determined in the total RNA isolated from the erythrocytes, leukocytes, and thrombocytes of the test whole blood sample. 13. The method of claim 1, wherein an at least 1.4 fold increase of the level of the at least one miRNA in the whole blood sample when compared to the reference level of the at least one miRNA is detected. 14. The method of claim 4, wherein the drug is selected from the group consisting of natalizumab, interferon beta 1a, interferon beta 1b, glatiramer acetate, alemtuzumab, fingolimod, dimethylfumarate, and mitoxantrone.

Details for Patent 10,428,382

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	05/07/2001		2032-03-07
Genzyme Corporation	LEMTRADA	alemtuzumab	Injection	103948	11/14/2014		2032-03-07
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	10/12/2004		2032-03-07